This study addresses the key roles of grp94, a major molecular chaperone in the endoplasmic reticulum (ER) in plasma cell biology and multiple myeloma (MM). MM is an incurable plasma cell neoplasm whose pathogenesis is closely linked to dysregulated unfolded protein response (UPR) in the ER. Constitutive activation of UPR in mice, as demonstrated by transgenic expression of a master UPR transcription factor XBP1s (a UPR-specific splice variant of X-box binding protein 1), causes myeloma. However, the underlying mechanism remains unknown. We have demonstrated that grp94 is an obligate chaperone for Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6). Furthermore, the persistence of plasma cells, as well as the development of myeloma in XBP1s-transgenic mice is critically dependent on grp94. The addiction of myeloma cells to grp94 was also demonstrated genetically and pharmacologically using multiple human myeloma cell lines. Furthermore, we found that grp94 is highly expressed in malignant plasma cells in MM. The higher level of grp94 is significantly associated with a worse clinical stage in MM. Thus, we hypothesize that the pathogenesis of MM is driven by both dysregulated UPR and canonical Wnt signaling, both of which converges onto grp94. We will address this hypothesis in Specific Aim 1, by taking advantage of multiple unique genetic tools we have generated including B cell-specific grp94 knockout mice and B cell-specific ?-catenin knockout mice. In Specific Aim 2, we will determine the roles of grp94 in the full clinical manifestation of myeloma in both novel MM mouse models and xenogenic human myeloma model. Moreover, in collaboration with Dr. Gabriela Chiosis from Sloan-Kettering Institute for Cancer Research, a novel class of grp94-specific inhibitors will be developed and investigated for their preclinical efficacy against myeloma. Overall, our studies will not only provide fundamental new insights into the roles of grp94 in the pathogenesis of MM, but also be instrumental in the development of grp94-targeted therapeutics against this disease.